6Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT

Corresponding author: Kitt Falk Petersen kitt.petersen{at}yale.edu

Abstract

Previous studies have reported that brain metabolism of acetate is increased more than two-fold during hypoglycemia in type
1 diabetic (T1D) subjects with hypoglycemia unawareness. These data support the hypothesis that upregulation of blood-brain
barrier monocarboxylic acid (MAC) transport may contribute to the maintenance of brain energetics during hypoglycemia in subjects
with hypoglycemia unawareness. Plasma lactate concentrations are approximately ten-fold higher than acetate concentrations,
making lactate the most likely alternative MAC as brain fuel. We therefore examined transport of [3-13C]-lactate across the blood-brain barrier and its metabolism in brain of T1D patients and non-diabetic control subjects during
a hypoglycemic clamp using 13C magnetic resonance spectroscopy. Brain lactate concentrations were more than fivefold higher (P<0.05) during hypoglycemia
in the T1D subjects compared to the control subjects. Surprisingly, we observed no increase in the oxidation of blood-borne
lactate in the T1D subjects, as reflected by similar 13C fractional enrichments in brain glutamate and glutamine. Taken together these data suggest that in addition to increased
MCA transport at the blood-brain barrier there may be additional metabolic adaptations that contribute to hypoglycemia unawareness
in patients with type 1 diabetes.